The present invention relates to a composition for inducing immunological tolerance to allergens in an individual of a mammalian species.
Clinicians are faced with an increasingly major problem due to the adverse effects accompanying the administration of certain drugs, particularly antibiotica in their patients. Many pharmaceutical compounds cause an allergic reaction as the patient forms drug specific reagenic antibodies or immunoglobulins, usually of the immunoglobulin class E. In this case immunoglobulin E (IgE) is produced by the body, in response to the presence of the foreign substance or antigen administered, and is specific to combat that antigen. Actually, there are two classes of allergic reaction; one being the humoral antibody production mentioned above wherein cells derived from the bone marrow (B-cells) are responsible for the production of reagenic antibodies of the class IgE. The second component of the immune system is a cell mediated reaction, wherein thymus derived lymphocytes (T-cells) infiltrate the body tissue causing an inflammatory response. In many cases, allergic reactions can be violent or even fatal if they cannot be reversed.
Currently, the most frequently employed solution to the clinical problem of drug allergy is to simply avoid the administration of the drug to which a patient has been found to be allergic.
Research into the field of drug allergy has been directed at inducing a tolerance within the body to certain allergens by administering the allergen in a specific form and dose so as not to trigger an allergic immune response. In particular, it has been found that small molecular sized allergens or haptens can be attached to certain carrier compounds and administered in doses sufficient to induce an immunological tolerance to the allergen.
Previous work done by one of the inventors and described in Transplantation Review 8, 76, 1972, has established the concept that antigens with a repetitive sequence of haptens on a linear molecule acting as a carrier provide the basis for this tolerogenic property.
One of the many problems associated with administering an allergen in attachment to a linear carrier is that the carrier itself, being foreign to the body, triggers an immune response to itself. Thus, a non-immunogenic carrier compound is necessary.
Another property desirable in the carrier is that it be able to disperse the attached allergen throughout the body, so as to induce a total body tolerance thereto. It will be understood that, to be soluble in the body fluids, the carrier in attachment to the allergen must be water soluble.
Thus far, several non-immunogenic or weakly immunogenic carriers have been discovered in this regard, which may serve as vehicles for tolerance induction to clinically relevant drugs, however no system as yet has satisfied all the requirements for a suitable carrier.
Autologous immunoglobulins have been suggested, wherein the hapten is conjugated with the body's own immunoglobulin. This tolerogen however faces the severe potential consequence of triggering an autoimmune reaction, wherein the body begins rejecting self.
Dextran, levan, ficoll and other carbohydrate carriers have been documented as potential tolerogens e.g. see J. G. Howard, B. M. Courtenay, Eur. J. Immunol., 4, 603, 1974. Unfortunately however, these carriers are all immunogenic at appropriate concentrations. This renders them potentially dangerous for clinical use. Thus when administered at concentrations below that for tolerance induction, they not only trigger an immune response to themselves but also to the hapten i.e. allergen attached to them.
It is known in the prior art to use carboxymethyl cellulose as a carrier matrix to immobilize biochemically active compounds, see for example U.S. Pat. No. 3,959,080 issued to Orth et al. For this purpose the carrier molecule must be water insoluble. This is accomplished by chemically cross-linking the polymeric strands of the carboxymethyl cellulose. In a water insoluble form this carrier matrix is not physiologically acceptable to the body.